The Hudson River (HR) Estuary contains Superfund sites for PCBs, TCDD, and heavy metals. Atlantic[unreadable] tomcod from the HR bioaccumulate high tissue burdens of these contaminants, sometimes to record levels.[unreadable] We have used tomcod as a model to evaluate the ecological effects of these pollutants and to study the[unreadable] mechanistic bases of their toxicities. Tomcod from throughout the HR are highly resistant to environmentally[unreadable] relevant doses of coplanar PCBs and TCDD, but not PAHs, at a variety of molecular and organismic[unreadable] endpoints including early life stage toxicities and aryl hydrocarbon receptor (AHR) pathway-mediated gene[unreadable] expression. The overall objectives of this renewal application are to further describe the extent of resistance[unreadable] n the HR tomcod population and to characterize its mechanistic basis. Although, at one time, tomcod from[unreadable] the HR exhibited remarkably elevated prevalences of hepatic tumors, the role of PCBs in this process was[unreadable] never empirically addressed. In controlled laboratory studies, we will determine if tomcod offspring from the[unreadable] HR, compared to those from sensitive populations, are resistant to hepatic neoplasia and related preneoplastic[unreadable] endpoints such as preneoplastic lesions, K-ras activation, ROS modified bases, bulky DMA[unreadable] adducts after exposure to PCBs and PAHs. Fish from highly contaminated locales, such as Superfund sites,[unreadable] are usually co-exposed to aromatic hydrocarbon and metal contaminants. Chemical analyses indicate that[unreadable] this is the case for tomcod from the HR. Yet, little is known of their interactive effects in vivo. We will[unreadable] investigate the effects of co-exposure to Gr VI on B[a]P-induced mutations, DMA adducts, and nucleotide[unreadable] excision repair at the K-ras oncogene which is frequently mutated in environmentally-exposed and[unreadable] chemically-treated fishes. The mechanistic basis of resistance will be addressed. Genetic polymorphisms will[unreadable] be characterized and their frequencies enumerated at AHR2, AHRR, and ARNT1 in tomcod from the HR and[unreadable] non-resistant populations. Those which show significant allelic differences will be functionally evaluated in[unreadable] assays which will quantify ligand binding, nuclear transformation, and transactivation. Multiple AHRs shown[unreadable] to exist in other fishes will be isolated and their structure and expression compared between the HR and[unreadable] sensitive populations. Novel proteins associated with AHRs or DREs will be identified using a proteomics[unreadable] approach and their expression compared between tomcod from the HR and susceptible populations.